Revisiting G-CSF Support for Hematologic Recovery after Autologous Transplantation in AML Patients

Research Article

Ann Hematol Oncol. 2017; 4(5): 1148.

Revisiting G-CSF Support for Hematologic Recovery after Autologous Transplantation in AML Patients

Oberson JS¹, Novak U¹, Taleghani BM², Baerlocher GM², Seipel K³, Mueller BU³, Leibundgut K4, Zimmerli S5 and Pabst T¹*

¹Department of Medical Oncology, University Hospital Bern, Switzerland

²Department of Hematology, University Hospital Bern, Switzerland

³Department of Clinical Research, University Hospital Bern, Switzerland

4Department of Pediatric Hemato-Oncology, University Hospital Bern, Switzerland

5Department of Infectious Diseases, University Hospital Bern, Switzerland

*Corresponding author: Thomas Pabst, Department of Medical Oncology, University Hospital Bern, 3010 Berne, Switzerland

Received: March 06, 2017; Accepted: April 06, 2017; Published: April 26, 2017


In acute myeloid leukemia (AML) patients, using granulocyte colonystimulating factor (G-CSF) to support hematologic recovery in induction and consolidation treatment reduces the number of febrile episodes and the duration of neutropenia and hospitalization. However, the benefit and safety of administering G-CSF to enhance hematologic recovery in AML patients after autologous stem cell transplantation (ASCT) have not been reported so far. At our center, it was our policy to administer G-CSF after ASCT in all AML patients. In June 2015, increasing economic pressure prompted us to omit G-CSF after ASCT. In this retrospective study, we assessed the effects of changing our strategy from applying G-CSF for hematologic recovery after ASCT (in 103 AML patients) to omitting G-CSF (12 patients). We found that administering G-CSF shortened the median duration until neutrophil recovery was >0.5 G/l after ASCT by four days (P=.0001), and patients with G-CSF tended to have fewer bacteremias (38.3% versus 66.6%; P=.0654). The median duration of hospitalization was two days longer in patients without G-CSF support (25 versus 23 days; P=.0603). According to the Swiss in-patient reimbursement system, the shorter hospitalization of +G-CSF patients resulted in decreased total costs per patient of 3305 CHF (48 Mio U of G-CSF), and 3367 CHF (30 Mio U). Finally, no differences were observed in disease free (P=.0938) and overall survival (P=.7999) rates between +G-CSF versus –G-CSF patients. Our data suggest that G-CSF support after ASCT is safe and associated with shorter time until neutrophil recovery, fewer bacteremia episodes, shorter hospitalization, and lower costs.

Keywords: Autologous; Transplant; AML; Leukemia; Recovery; Prognosis; Survival; Granulocyte-colony Stimulating factor; G-CSF; Consolidation


Two cycles of induction chemotherapy yield complete remission (CR1) in up to 80% of young patients with newly diagnosed acute myeloid leukemia (AML) [1]. However, without subsequent treatment most patients will eventually relapse within few months. Consequently, they are offered consolidation treatment in CR1 with either conventional chemotherapy, autologous or allogeneic transplantation [2-4]. Among these options, high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) can be applied to consolidate CR1 in AML patients who have favorable or intermediate risk cytogenetic and molecular abnormalities [5-8].

Despite autologous stem cell support, HDCT inevitably causes transient, but relevant cytopenias, with neutropenia exposing patients to the risk of infections, morbidity, and, rarely, a fatal outcome. Thus, shortening the duration of neutropenia with granulocytecolony stimulating factor (G-CSF) after ASCT is expected to reduce infectious complications [9]. In fact, G-CSF given to support hematologic recovery following induction chemotherapy in AML patients has been shown to reduce the duration of neutropenia, the number of febrile episodes, the duration of hospitalization and the requirement for parenteral antibiotics [10-13]. In contrast, it is of no benefit if given together with chemotherapy as a priming strategy to improve survival rates [14].

The situation in AML-as compared to lymphomas or myeloma -is complicated by the fact that myeloid blasts usually express receptors for hematopoietic growth factors such as G-CSF and granulocyte macrophage-colony stimulating factor (GM-CSF). In AML patients, treatment with myeloid growth factors has therefore been hampered by concerns on potential stimulation of leukemic cell growth. Consequently, randomized trials have analyzed whether the use of myeloid growth factors can reduce the duration of chemotherapyinduced neutropenia in AML patients without compromising antileukemic treatment. However, no consistent detrimental effects on survival have been reported with myeloid growth factors given to promote hematologic recovery following induction chemotherapy or after consolidation chemotherapy [10-13]. In contrast, the use of myeloid growth factors in AML patients to enhance hematologic recovery after HDCT with ASCT has not been similarly studied. In fact, it is largely unknown whether applying myeloid growth factors are safe after ASCT in AML patients.

At our center, it was our policy to support hematologic recovery with G-CSF after ASCT in AML patients. In June 2015, however, increasing economic pressure prompted us to omit G-CSF after ASCT thereby saving the costs of G-CSF. However, the introduction of biosimilar G-CSF compounds forced prizes for G-CSF to plummet and largely eliminated the cost argument in the meantime. In the present study, we therefore re-evaluated the use of G-CSF after ASCT in AML patients comparing two consecutive cohorts of patients with G-CSF support (+G-CSF; January 2004 until June 1, 2015) after ASCT versus without G-CSF (-G-CSF; from June 2015 until November 2016).

Patients and Methods


In this single center retrospective analysis, we investigated consecutive AML patients in CR1 receiving HDCT with ASCT after two cycles of induction chemotherapy at the University Hospital of Bern, Switzerland between January 2004 and November 2016. Patients underwent HDCT with ASCT if the genomic risk assessment indicated good-risk, intermediate-risk (in the absence of an HLA-identical sibling donor), or bad/very bad risk AML (in the absence of a sibling and an unrelated matched donor). Risk assessment was performed according to the European Leukemia Net (ELN) classification. The clinical characteristics of the patients are summarized in Table 1. This study was approved by the local ethics committee of Bern, Switzerland (decision number #220/15).


The patients were uniformly treated within subsequent protocols of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) / Swiss Group for Clinical Research (SAKK), including the SAKK/HOVON-42, -92, -102 and -132 protocols. Patients received cytarabine 200 mg/m2 on days 1-7 and idarubicin 12 mg/m2 days 1-3 in induction cycle 1; and cytarabine 1000 mg/m2/q12h days 1-6 and amsacrin 120 mg/m2 days 1-3 were given in cycle 2, which was also used for subsequent mobilization of peripheral blood stem and progenitor cells (PBSC). G-CSF stimulation at 10 µg/kg body weight (b.w.) was initiated on the first day of cycle 2 when neutrophils increased above 0.5 G/L. Stem cell collection was performed on the first day when the number of peripheral circulating CD34+ cells exceeded 20,000/ ml. For HDCT, patients received oral busulfan 4 mg/kg b.w./day on days -6 until -3, and intravenous cyclophosphamide 60 mg/kg/day on days -2 and -1. A minimum of 2.0x10^6 CD34+ cells/kg b.w. was transfused at the day of autologous stem cell transplantation (day 0).

Before June 2015, patients received 30 Mio U (<78kg b.w.) or 48 Mio U (=78kg) of G-CSF as a once daily s.c. injection from days +6 to +12 after ASCT. In June 2015, we changed our strategy and committed to reevaluate it after 12 treated patients; thus, patients after June 2015 received no G-CSF for hematologic recovery after ASCT. Patients in the two cohorts were evaluated for hematologic recovery, number of platelet and erythrocyte transfusions, febrile episodes and bacteremias, duration of hospitalization and costs.

All patients undergoing HDCT with ASCT routinely had antiviral (oral acyclovir 500 mg twice daily) and antifungal prophylaxis (oral fluconazole 400mg once weekly), and oral sulfamethoxazol/ trimethoprim 800/160 mg three times per week. No routine antibiotic prophylaxis was given. Hyperuricemia prophylaxis with 300 mg oral allopurinol was applied on days -7 to -1. Patients received platelet and red cell transfusions when platelets fell <10 G/L or if clinically indicated (bleeding, need for interventions), and hemoglobin was <80 g/L, respectively. Patients were hospitalized for the entire HDCT/ ASCT procedure and dismissed after hematologic recovery and adequate physical reconditioning.


Overall survival was defined as the time from ASCT until death from any cause or until the last follow-up. Disease-free survival was defined as the time from the date of ASCT until the first progression of AML or the last follow-up, whichever occurred first. Follow-up was defined as the time from ASCT until the last documented patient visit in our department. Patients still alive or lost to follow-up were censored at the last date when they were known to be alive.

Statistical analysis

Survival curves were analyzed using the log-rank (Mantel- Cox) test. The unpaired t-test was applied to compare continuous variables. The Mann- Whitney test was used to compare the median of parameters. In order to compare specific parameters between the two groups, the two proportion test (based on the N-1 chi-square test) was applied. All P-values were two-sided, indicated with the P, and not adjusted for multiple testing, unless explicitly indicated. A P-value below 0.05 was considered significant. The cut-off date for this analysis was November 1, 2016. For the statistical analysis, GraphPad Prism Version 5.0c (GraphPad Software Inc., La Jolla, CA, USA) was used.


Hematologic recovery

From January 2004 to June 2015, 103 AML patients in CR1 were uniformly treated with G-CSF after ASCT, whereas 12 additional consecutive AML patients underwent HDCT with ASCT after June 2015 without G-CSF support. We observed that the median time from ASCT (day 0) until neutrophil recovery >0.5 G/L was 12 days (range 9-57 days) for +G-CSF patients and 16 days (range 11-19 days) without G-CSF (P=.0001) (Figure 1A). Similarly, the median time until neutrophil recovery >1.0 G/l was 13 days (range 10-57 days) for +G-CSF patients and 18 days (range 11-54 days) without G-CSF (P=.0020) (Supplementary Figure 1A), whereas no differences were observed for platelet recovery >20 G/L (P=.7017) (Supplementary Figure 1B), >50 G/L (P=.9145), or >100 G/L (P=.6155). Also, the median number of platelet transfusions (three versus two units; P=.9563) and of red blood cell transfusions (two units in both cohorts; P=.7351) were comparable.

Citation:Oberson JS, Novak U, Taleghani BM, Baerlocher GM, Seipel K, Mueller BU, et al. Revisiting G-CSF Support for Hematologic Recovery after Autologous Transplantation in AML Patients. Ann Hematol Oncol. 2017; 4(5): 1148. ISSN:2375-7965